Exploring the Link Between Allergies and Neurological Diseases: Unveiling the Hidden Connections

Abstract

The interplay between allergic diseases and neurological disorders has gained increasing attention over the past decades, highlighting potential shared pathophysiological pathways. Allergic diseases, including asthma, eczema, and allergic rhinitis, are characterized by chronic inflammation and immune dysregulation, which may impact the pathogenesis of certain neurological conditions. Emerging evidence suggests that conditions such as multiple sclerosis (MS), migraine, epilepsy, neurodegenerative diseases, and neurodevelopmental disorders may be influenced by systemic inflammation and altered immune responses associated with allergies. The purpose of this paper is to provide an overview of current epidemiological evidence suggesting a relationship between allergic and neurological diseases. Understanding the complex interactions between allergic and neurological diseases could provide new insights into their aetiology and reveal novel therapeutic targets, paving the way for integrated approaches in managing comorbid allergic and neurological conditions, ultimately improving patient outcomes and quality of life.

1. Introduction

The relationship between allergic diseases and neurological disorders has gained scientific attention due to potential shared pathophysiological mechanisms linking these conditions. Allergic diseases such as asthma, eczema, and allergic rhinitis are characterized by immune dysregulation and chronic inflammation, which may influence central nervous system (CNS) processes. Similarly, numerous neurological disorders, including multiple sclerosis (MS), Parkinson’s disease (PD), Alzheimer’s disease, neurodevelopmental disorders, and epilepsy, involve neuroinflammation and immune-mediated mechanisms that overlap with pathways involved in allergic responses.

A hallmark of allergic diseases are IgE-mediated inflammation and the type 2 immune response. The hyperactivation of immune cells such as T-helper type 2 (Th2) cells, leads to the release of cytokines like interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-9 (IL-9), and interleukin-13 (IL-13) [1]. Moreover, interleukin-17 (IL-17) produced predominantly by T-helper type 17 (Th17) cells exacerbates allergic airway inflammation by stimulating the production of multiple pro-inflammatory factors, including cytokines, chemokines, and adhesion molecules. This process subsequently promotes the recruitment and activation of neutrophils and Th2-driven eosinophils [2,3]. Interestingly, IL-17 has been strongly linked to neuroinflammation, which can disrupt the integrity of the blood-brain barrier (BBB), alter the structure and distribution of glial cells and neurons, and disrupt synaptic plasticity [4]. IL-17 has also been shown to trigger microglial activation, intensifying neuroinflammation and neurodegeneration in animal models of Parkinson’s disease, as well as cognitive impairment in aged rats [5,6]. Finally, IL-17 signalling in astrocytes has been found to promote glutamate excitotoxicity and the consequent neurodegeneration [7].

Beyond classical systemic inflammation, allergic responses may influence CNS function through indirect pathways, including the gut-brain axis [8,9]. Studies using animal models highlight the role of mucosal mast cells and their interaction with calcitonin gene-related peptide-immunoreactive (CGRP-ir) neurons in the development of food allergies [10,11,12]. Additionally, a study by Yashiro et al. identified functional high-affinity IgE receptors (FcεRIs) on murine enteric neurons and reported that stimulation with an IgE-antigen complex increased intracellular Ca²⁺ concentrations in isolated myenteric neurons. This suggests that FcεRIs can directly activate myenteric neurons. Furthermore, through interactions with mucosal mast cells, IgE-antigen-activated myenteric neurons are believed to contribute to the exacerbation of food allergy pathology [13]. These findings have been comprehensively summarized by Sindher et al. [14].

Investigating the interplay between allergic and neurological diseases offers a promising avenue to uncover shared etiological factors and identify novel therapeutic strategies that address both conditions comprehensively. The purpose of this paper is to systematically review and synthesize current evidence from epidemiological studies, with a focus on identifying recurring immune signatures and possible causal relationships between allergic and neurological conditions. To identify articles eligible for inclusion, electronic databases (Pubmed, Medline) has been searched with the main focus on original research that has been published over the past two decades.

2. Multiple Sclerosis

Multiple sclerosis (MS) is a progressive neuroinflammatory condition with a complex pathophysiology. Numerous factors contribute to the progression of inflammation and neurodegeneration in MS, including genetic predisposition, immune system imbalances, and environmental influences such as vitamin D deficiency, as well as infections [15]. According to the conventional T-helper (Th) cell paradigm, an increase in Th1 activity appears to promote autoimmunity, whereas an upregulation of Th2 responses favors humoral immunity. Consequently, this could lead to the mutual exclusivity between allergic diseases (AD) and MS, so that individuals with AD would have a lower susceptibility to autoimmune disorders like MS [16,17]. However, more up to date findings have suggested, that Th 17 may play a role in the underlying pathogenesis of both autoimmune and allergic diseases [18]. Experimental studies confirmed that autoimmune demyelination and AD share common cells and molecular mechanisms [19]. A post mortem analysis of MS lesions showed a high concentration of transcripts of genes encoding inflammatory cytokines, particularly interleukin-6 (IL-6) and IL -17, and interferon gamma (IFN- γ) [20]. Another common pathophysiological trait of AD and MS has been investigated by Gregory at al. [21] Mast cells, which are known to play an important role in allergy and parasitic infections, were proven to contribute to the severity of the rodent model of MS, experimental autoimmune encephalomyelitis (EAE). Mast cells can influence the autoreactive T cell response, including IFN-γ production and increases in CD44 and CD11a expression, promoting myelin damage and disease exacerbation. Subsequent studies investigated the role of histamine axis in the MS pathology [22,23] Histamine regulates the maturation and activation of leukocytes and directs their migration to target sites where they cause inflammation, which stimulates the development of allergic-related inflammatory diseases [24]. On the other hand, in the animal EAE model histamine showed a potentially beneficial effect by inhibiting activation of myelin-autoreactive T cells and their ability to traffic through the inflamed BBB, which makes H1 histamine receptor (H1R) and H2 histamine receptor (H2R)a potential therapeutic target in autoimmune diseases.

A recent comprehensive systematic review by Aielli et al. [25] explored the relationship between MS and AD. Yet, the findings of the included epidemiological studies have not establish an unequivocal inverse correlation between AD and MS. Tremlett et al. conducted a retrospective case-control study involving 320 MS patients and 320 matched controls in Wales. Their analysis revealed a statistically significant inverse association between MS and asthma. Nonetheless, no significant relationship was found between MS and other Th2-associated conditions, such as eczema and dermatitis [16]. On the contrary, the study conducted by Ponsonby et al. in Australian and Tasmanian population showed a statistically significant positive correlation between MS and asthma [26]. Subsequent case-control studies in the UK and US population by Alonso et al. revealed no correlation between MS and different types of AD, including allergies, asthma, rhinitis, eczema, and others [27,28]. An Italian study involving 200 individuals with MS and 200 controls observed that MS patients had a significantly lower likelihood of suffering from allergic respiratory diseases (ARDs) and allergic rhinitis after adjusting for environmental factors. Moreover, MS tended to be less severe in patients with ARDs [17]. An overview of the studies investigating the relationship between MS and allergic diseases is presented in

Table 1. An overview of studies investigating the relationship between multiple sclerosis and allergic diseases. The studies are presented in chronological order.

Study	Study Group	Allergic Diseases	Results
Tremlett et al. (2002) [16]	346 MS patients in Wales	Asthma	Inverse association between MS and asthma compatible with a Th1/Th2 imbalance.
Alonso et al. (2006) [28]	163 patients with MS in the UK	Allergic rhinitis, hay fever, urticaria, eczema, atopic dermatitis	1. No association between allergies and MS 2. H1R activation was associated with decreased MS risk
Ponsonby et al. (2006) [26]	136 patients with MS in Australia	Asthma	Asthma rates were significantly higher in individuals with MS prior to symptom onset.
Alonso et al. (2008) [27]	298 women with MS in the USA	Allergy to pollens, house dust, animal dander, food, drug	No association between allergies and MS
Pedotti et al. (2009) [29]	423 adults with MS in Italy	Asthma, rhinitis, conjunctivitis, contact and atopic dermatitis, food, drug, insect sting allergy	Inverse association between MS and allergic diseases, especially asthma.
Bergamaschi et al. (2009) [17]	200 MS patients in Italy	Allergic respiratory diseases	1. Inverse association between MS and allergic diseases 2. MS tended to be less severe in individuals with allergic respiratory diseases
Ramagopalan et al. (2010) [30]	6638 MS patients in Canada	Cow’s milk allergy	Childhood cow’s milk allergy is not associated with MS
Karimi et al. (2013) [31]	40 adults with MS in Iran	rhinitis, conjunctivitis, urticaria and eczema, asthma	No significant relationship between allergy history and IgE levels and MS
Sahraian et al. (2013) [32]	195 MS patients in Iran	Asthma, allergic rhinitis, urticaria/angioedema, eczema, food, drug and non specific agents allergies	Inverse association between MS and allergic diseases
Hughes et al. (2013) [33]	282 adults with first central nervous system demyelination (FCD) in Australia	Asthma, hay fever, eczema	No association between allergies and FCD
Ashtari et al. (2013) [34]	40 MS patients in Iran	Cow’s milk allergy	No association between cow’s milk allergy and MS
Mansouri et al. (2014) [35]	1403 MS patients in Iran	Conjunctivitis, rhinitis, urticaria, asthma, food, drug, pollens, house dust, animal dander allergies	History of any allergic condition was a risk factor of MS.
Skaaby et al. (2015) [36]	35 adult MS patients in Denmark	Atopy with present serum IgE antibodies against common inhalant allergens	No statistically significant associations between atopy and autoimmune disease
Manouchehrinia et al. (2015) [37]	680 MS patients in England	Asthma	No difference in the prevalence of asthma between MS cohort and the England general population.
Ren et al. (2017) [38]	829 MS patients in the USA	Respiratory tract and other allergies	Inverse association between MS and allergic diseases.
Bourne et al. (2017) [39]	271 MS children and adolescents In the USA	Asthma, food, drug and environmental allergies	Allergies and asthma are not associated with pediatric MS.
Fakih et. al (2019) [40]	1349 MS patients in the UK	foods, drugs and environmental allergies	MS patients with food allergy had more relapses and more lesions.
Krishna et. al (2019) [41]	A total of 3,225,758 patients with allergic diseases in the UK	Allergic rhinitis/conjunctivitis, eczema, asthma	No significant association between allergic diseases and MS.
Hill et al. (2019) [42]	141,880 MS patients in the USA	Asthma	Asthma is significantly more common in those with MS than in the general population.
Albatineh et. al (2020) [43]	128 Kuwaiti MS patients	Food allergy	No significant association between food allergy and MS.
Chen et al. (2020) [44]	929 MS patients in Australia	Allergies, not specified	Significant association between allergies and MS.
Sorensen et al. (2021) [45]	2012 MS patients in the USA	Asthma	Asthma is common in MS patients. Asthmatic patients were more likely to be female, obese, hypertensive, and living in neighborhood of medium/low income, and less likely to be on interferons or glatiramer acetate.
Lo et al. (2021) [46]	1518 MS patients in Australia	Allergies, not specified	No significant association between allergies and MS.

MS–multiple sclerosis; H1RA-H1 histamine receptor.

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3. Neurodegenerative Diseases

Parkinson’s disease (PD) is a chronic neurological disorder characterized by a wide spectrum of motor and non-motor symptoms and a complex pathophysiology [47]. Neuroinflammation has been proposed as one of the factors in pathological progression of PD [48]. The presence of the neuroinflammatory processes and its role in PD has been supported by numerous histological, neuroimaging, and laboratory studies of the peripheral blood of the PD patients [49]. Neurodegenerative diseases involve activation of microglia, the brain’s resident immune cells, and the release of inflammatory mediators, including tumour necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β), which contribute to neuronal damage and death [50]. Allergic comorbidities are often present in patients with neurodegenerative diseases [51]. It is believed, that chronic allergic inflammation may exacerbate neuroinflammatory processes, promoting the progression of diseases like Parkinson’s disease and Alzheimer’s Disease [52,53].

On a molecular level, the microtubule-associated protein tau accumulates as neurofibrillary tangles in Alzheimer’s disease, ultimately leading to neurodegeneration. Sarlus et al. found that allergy increases phosphorylation of tau protein in the rodent brain [54]. Regarding the epidemiological studies, Chen at al. [55] analysed the risk of dementia among 11,030 participants aged more than 45 years with asthma in Taiwan. The group noted, that asthma was associated with an increased risk of developing any dementia, and Alzheimer’s disease. A subsequent study by Woo et al. [56] focused on the association of all-cause dementia and Alzheimer’s disease in patients with atopic dermatitis in a group of 38,391 adults in Korea. In fact, the group noted a statistically significant increased risk of dementia in individuals suffering from atopic dermatitis. Recently, Hu et al. [57] indicated that elderly asthma was a predisposing factor of a cognitive dysfunction, independent of sex, age, race, ethnicity, BMI, and diabetes in the American patients. Additionally, mediation analysis suggested that asthma might contribute to cognitive dysfunction through the involvement of systemic immune inflammation index. Joh et al. [58] examined the relationship between asthma, allergic rhinitis, and atopic dermatitis and the risk of developing dementia, including all-cause, Alzheimer’s disease and vascular dementia. The findings indicated that individuals with allergic diseases had a higher risk of all-cause dementia compared to those without allergic diseases. Notably, the risk increased with the number of comorbid allergic conditions, suggesting a cumulative effect. These results were supported by the research of Wang et al. [59]

Regarding Parkinson’s disease, Bower et al. [60] conducted a case-control study encompassing 196 PD cases and 196 matched controls. The group found that individuals with allergic rhinitis were 2.9-fold more likely to develop PD later in life compared to those without the condition. Some years later, Cheng et al. [61] investigated the relationship of asthma and PD utilizing data of 10,455 patients with asthma from the Taiwan National Health Insurance Research Database. This research also revealed a positive correlation between PD and AD, showing that individuals with asthma had an elevated risk of developing PD later in life. Moreover, greater asthma severity correlated with a higher risk of subsequent PD. In the newest study by Nam et al. [62] the data of 398,936 participants were extracted from the Korean National Health Insurance Service database in order to examine the relationship between allergic diseases—including allergic rhinitis, asthma, and atopic dermatitis—and the risk of developing PD. The findings indicated that individuals with allergic diseases had a higher risk of developing PD compared to those without allergies, with allergic rhinitis showing a particularly significant association. This risk persisted even among individuals with healthy lifestyle behaviours.

4. Epilepsy

Emerging research has identified a potential association between AD and epilepsy, suggesting that immune system dysregulation may play a role in seizure susceptibility. Several studies have explored this link, providing insights into the complex interplay between allergic conditions and epilepsy. A group of researches from China summarized the published studies in a systematic review and conducted a metanalysis of the extracted data. The pooled results indicated an 81% increase in the prevalence of epilepsy in individuals with asthma compared to those without, suggesting a notable link between these conditions [63]. The studies investigating the relationship between epilepsy and allergic diseases are summarized in

Table 2. An overview of studies investigating the relationship between epilepsy and allergic diseases. The studies are presented in chronological order.

Study	Study Group	Allergic Diseases	Results
Frediani et al. (2001) [64]	72 children in Italy	Food and drug allergies, asthma, eczema, rhinitis	1. A significantly higher incidence of allergy to cow’s milk and asthma in the epileptic children. 2. Significantly higher rates of eczema in the mothers and rhinitis in the siblings of the epileptic children.
Kobau et al. (2004) [65]	161 adults in the USA (Georgia and Tennessee)	Asthma	Significantly higher incidence of asthma among adults with seizures.
Strine et al. (2005) [66]	426 adults in the USA	Asthma	Significantly higher incidence of asthma among adults with seizures.
Elliott et al. (2008) [67]	97 adults in the USA	Asthma	Asthma rates were significantly higher in individuals with epilepsy.
Babu et al. (2009) [68]	250 adolescents and adults (16 to 60 years) in the USA	Asthma	Asthma rates were not significantly higher in individuals with epilepsy.
Karlstad et al. (2012) [69]	37,060 children and adults (8–29 years) with asthma in Norway	Asthma	Significantly higher incidence of epilepsy and migraine among patients with asthma.
Silverberg et al. (2014) [70]	944 children with asthma in the USA	Asthma, eczema, hay fever, food allergies	The US prevalence of epilepsy is associated with allergic diseases in children.
Chen et al. (2014) [71]	35,312 children and adults with atopic dermatitis in Taiwan	Atopic dermatitis	Subjects with atopic dermatitis were associated with an increased risk of developing epilepsy in later life.
Lin et al. (2014) [72]	991 children (1 month–2 years) in Taiwan	Asthma	Significantly higher cumulative incidence of asthma occurrence in children with more febrile seizure-related medical visits.
Kauppi et al. (2015) [73]	251,540 adults and children with asthma in Finland	Asthma	The most common other reimbursed chronic conditions in addition to asthma in the youngest age groups were epilepsy or other comparable convulsive disorders.
Strom et al. (2016) [74]	63,064 children with one or more allergic diseases in the USA	Asthma, hay fever, eczema, and food allergies	1. Children with hay fever, eczema, and food allergies had higher odds of experiencing seizures. 2. No significant association between asthma and seizures.
Chiang et al. (2018) [75]	150,827 children and adults with asthma in Taiwan	Asthma	The asthma group exhibited a higher epilepsy incidence than did the control group
Machluf et al. (2020) [76]	113,671 Israeli adolescents with asthma	Asthma	Asthma was associated with epilepsy and migraine.

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Frediani et al. investigated the relationship between AD and epilepsy in 72 children and their immediate families. The study showed significantly higher rates of eczema in the mothers and rhinitis in the siblings of the patients studied. Moreover, a higher incidence of allergic pathologies in both of these groups were noted. In the epileptic children, a significantly higher incidence of allergy to cow’s milk and asthma were observed when compared to controls. Similarly, Silverberg utilizing data from the 2007–2008 National Survey of Children’s Health in the United States found that children with allergic diseases, including asthma, atopic dermatitis (eczema), hay fever, and food allergies, had increased odds of being diagnosed with epilepsy. The study reported that the presence of one or more allergic conditions was associated with a higher prevalence of epilepsy et al. [70]. Strine et al. [66] analyzed data obtained from adults who participated in the 2002 National Health Interview Survey (NHIS) in the USA, which showed a significantly higher incidence of asthma among adults with seizures. Another study analysing data from the NHIS found that children with hay fever, eczema, and food allergies had higher odds of experiencing seizures. The research indicated that the risk of seizures increased with the number of comorbid allergic diseases, highlighting a cumulative effect [74].

5. Migraine

Migraine is a complex neurological disorder characterized by recurrent headaches often accompanied by sensory disturbances, nausea, and autonomic symptoms. While the exact pathophysiological connection remains incompletely understood, growing epidemiological evidence suggests a significant link between migraine and allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis [77]. Histamine, one of the earliest identified mediators of allergy, is considered a key pathophysiological link to migraine, primarily due to its vasodilatory effects [78].

Several systematic reviews and meta analyses showed that allergic diseases are associated with an increased risk of migraine and other type of headaches [45,79]. The studies investigating the relationship between allergic diseases, primarily between asthma and migraine, are summarized in

Table 3. An overview of studies investigating the relationship between migraine and allergic diseases. The studies are presented in chronological order.

Study	Study Group	Results
Davey et al. (2002) [80]	64,678 adults in the UK	Significant association between migraine and asthma.
Aamodt et al. (2007) [81]	A total number of 51,383 adult individuals in Norway	Both migraine and nonmigraine headache were 1.5 times more likely among individuals with asthma, asthma related symptoms, hay fever, and chronic bronchitis.
Becker et al.(2008) [82]	51,688 adult migraineurs in the UK	The risk of developing asthma was not higher for patients with migraine diagnosis, regardless of triptan use.
Le et al. (2011) [83]	46,418 adult twins Denmark	Conditions with a positive association to migraine were asthma, stroke, and epilepsy. The concomitant diseases were more frequent in female patients with aura.
Chen et al. (2012) [84]	681 adult patients with chronic migraine in Taiwan	Individuals with chronic migraine had significantly increased risks of cardiovascular disease, sinusitis, asthma, gastrointestinal ulcers, vertigo and psychiatric disorders by 1.6–3.9-fold.
Czerwinski et al. (2012) [85]	3731 pregnant women with migraine in the USA	Migraineurs had 1.38-fold increased odds of asthma as compared with non migraineurs). The odds of hypertensive disorders of pregnancy were highest among women with comorbid migraine-asthma.
Lateef et al. (2012) [86]	6843 adolescents with headache in the USA	Adolescents with migraine more often reported asthma (or seasonal allergies compared to those with non-specific headache.
Peng et al. (2016) [87]	25,560 patients more than 12 years old with asthma in Taiwan	The risk of migraine in the asthmatic group was 1.45-fold higher.
Tsiakiris et al. (2017) [88]	462 individuals with asthma and allergic rhinitis in Sweden	Allergic asthma and rhinitis are associated with migraine, fibromyalgia, and irritable bowel syndrome.
Peng et al. (2018) [89]	6647 adult patients with migraine in Taiwan	Adult patients with migraine have significantly higher risk of asthma.
Graif et al. (2018) [90]	A total of 113,671 adolescents in Israel	A significant association between migraine and both asthma and allergic rhinitis.
Wei et. al. (2018) [91]	16,130 children with migraine in Taiwan	Children with preexisting atopic dermatitis, allergic conjunctivitis, allergic rhinitis, and asthma had a significantly higher risk of devel-oping migraines, with a cumulative effect
Kim et al., 2019 [92]	113,059 adult asthma participants 36,044 migraine participants	Asthma and migraines in adults are reciprocally associated.
Buse et al., 2020 [93]	15,133 adult individuals with migraine in the USA	1. The migraine group was at least twice as likely to experience allergies/hay fever and asthma. 2. Severe headache pain intensity was associated with an increased risk of allergy but not with asthma. 3. Increasing migraine frequency was associated with increasing risk for allergy/hay fever and asthma.

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In the Head-HUNT Study [81], a large cross-sectional population-based study conducted in Norway, a total number of 51,383 individuals completed two questionnaires, including more than 200 health-related questions. The results showed that both migraine and nonmigraine headache were approximately 1.5 times more likely to occur among in individuals with current asthma, asthma related symptoms, hay fever, and chronic bronchitis than in those without. These findings are consistent with the research by Le at al. [83], which investigated comorbidities of migraine and confirmed that allergies and asthma show positive association, especially to migraine with aura. Other common concomitant diseases of migraine were stroke and epilepsy, and they were more frequent in females. Subsequently, Kim et al. [92] conducted a large observational cohort study investigating the bidirectional association between asthma and migraine in adults in Korea. The first part of the study included 113,059 participants with asthma, matched with 113,059 control participants. In the second part of the study 36,044 individuals with migraine were matched with 114,176 control participants. Data were obtained from the Korean National Health Insurance Service-National Sample Cohort, with both asthma and migraine defined based on ICD-10 codes. The findings confirmed a reciprocal association between asthma and migraine. Similar results were obtained in the MAST Study [93]. The MAST Study was a prospective, web-based survey conducted in the USA, that included 15,133 people with migraine (using modified International Classification of Headache Disorders-3 beta criteria) and 77,453 controls without migraine in order to explore the comorbidities of migraine. The migraine group was at least twice as likely to experience allergies/hay fever and asthma when compared to the control group. Moreover, a higher migraine frequency was associated with increasing risk for allergy/hay fever and asthma. On the other hand, Czerwinski et al. [85] aimed to explore the relationship between migraine and asthma in a cohort of 3731 pregnant women. Their findings indicated that individuals with migraine had 1.38 times higher odds of developing asthma compared to those without migraine. Moreover, the risk of hypertensive disorders during pregnancy was highest among women with both migraine and asthma. The correlation between allergic diseases and different types of headaches in children and adolescences has been also thoroughly examined over the past two decades. A cross-sectional, population-based survey conducted among 8817 adolescents in Norway by Saunes et al. [94] revealed a significant association between headache and neck or shoulder pain and migraine for both sexes. Similarly, Graif et al. [90] explored the relationship between asthma and migraine in a cross-sectional study of over 110,000 adolescents in Israel. The researchers concluded, that migraine headaches occurred significantly more frequently both in individuals with asthma and with allergic rhinitis. To investigate the connection between AD—including atopic dermatitis, allergic conjunctivitis, allergic rhinitis, and asthma—and the future risk of migraine, Wei et al. [95] recruited 16,130 children with migraine and 64,520 matched controls without a history of migraine. Their findings revealed that children with preexisting allergic conditions had a significantly higher risk of developing migraines. Allergic rhinitis showed the strongest association with migraine and cumulative effect was observed.

6. Neurodevelopmental Disorders

Immune dysregulation and inflammation, associated with both genetic and environmental factors, have been shown to play an important role in the pathophysiology of both allergic and neurodevelopmental disorders—such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD)—indicating shared underlying mechanisms in these conditions [96,97]. Most importantly, allergic conditions trigger the activation of mast cells, and thus the production of a number of biologically active substances. This, in turn, leads to the malfunction of the blood-brain barrier (BBB) [98]. The presence of circulating autoantibodies directed against fetal brain proteins further supports the notion of increased BBB permeability in individuals with ASD [99]. The study conducted by Mostafa and al. showed that elevated serum brain auto-antibodies were found in 78.5% of autistic children and their presence significantly correlated with allergic symptoms [100]. Furthermore, mast cells stimulate the release of tumor necrosis factor (TNF) and interleukin-6 (IL-6), both of which have been identified in the brain and cerebrospinal fluid (CSF) of individuals with ASD [101]. Additionally, mast cells secrete transforming growth factor-β (TGF-β) as well as increase the levels of IL-17 [102]. Increased Th17 cells and related cytokine IL-17 were observed in ASD children, especially with comorbid asthma [103,104]. Further, mast cells have been shown to interact with microglia in the brain, leading to their proliferation and activation, leading to neuroinflammation [105,106]. When activated, microglia may also affect neuronal connectivity [107,108].In animal studies, it has been demonstrated that maternal immune activation can increase levels of pro-inflammatory cytokines that cross the placenta, leading to lifelong neuropathology and altered behaviors in offspring [109,110]. What is more, the transplacental passage of maternal IgG antibodies, including maternal antibodies to human fetal brain, indicates a potential role of maternal autoantibodies in the etiology of ASD [110,111] In line with the findings, numerous epidemiological studies have demonstrated the link between neurodevelopmental disorders and both maternal and infant allergic diseases, including asthma, eczema, food allergies, and food intolerance [112,113,114,115,116,117,118,119,120,121,122,123,124,125].

Chen et al. [120] conducted a longitudinal study utilizing the Taiwan National Health Insurance Research Database and included 14,812 individuals diagnosed with any atopic disease (asthma, atopic dermatitis, allergic rhinitis, or allergic conjunctivitis) before the age of 3 and 6944 non-atopic controls. The study showed, that the presence of any atopic disease in early childhood increased the risk of developing ADHD and ASD later in life. Moreover, a greater number of atopic comorbidities correlated with a higher risk of developing ADHD and ASD. Similarly, a population-based, cross-sectional study by Xu et al. in the US pediatric population showed that the prevalence of reported food, respiratory, and skin allergies was higher in children with ASD [123]. The CHARGE study, which enrolled 560 children with confirmed ASD and 391 typically developing children, did not confirm that the prevalence of asthma and overall allergies was higher in children with ASD when compared to controls. Nonetheless, food allergies were significantly associated with ASD and allergy in children with ASD was associated with higher stereotypy scores as measured by the Aberrant Behavior Checklist [125].

7. Discussion

The relationship between allergic diseases and neurological disorders remains a topic of growing interest, with experimental studies suggesting shared pathophysiological pathways. While the literature supports immunological links between allergy and neurological disorders, not all studies report consistent epidemiological associations. In some cases, allergic conditions may indeed be an epiphenomenon occurring in genetically or immunologically predisposed individuals rather than a causative factor. Moreover, the discrepant findings may be attributed to several factors, including genetic heterogeneity among study populations, varying diagnostic criteria for both allergic and neurological conditions, as well as differences in study design and sample size. Additionally, the lack of standardized assessment of clinical severity and inconsistent use of statistical analyses further complicates direct comparisons across studies.

Therefore, it is crucial to interpret findings within the context of study design, population characteristics, and disease definitions. In case of MS, larger, well-designed studies are necessary to confirm or refute the Th1/Th2 paradigm in this context.

Similarly, multiple studies have reported an inverse relationship between glioma risk and a history of allergic conditions. Some findings suggest that respiratory allergies may be particularly significant in glioma susceptibility. However, this protective effect appears to vary by ethnicity and requires further exploration [126,127,128,129,130]. On the other hand, many neurological disorders are believed to be positively correlated with allergic conditions. Although the exact pathophysiological pathways remain unclear, evidence suggests that allergic inflammation may contribute to the development of neurodegenerative diseases. Correspondingly, the association between allergic diseases and epilepsy has gained attention, with findings indicating that allergic inflammation may play a role in epileptogenesis through systemic immune activation, blood-brain barrier disruption, and neuroinflammation. Also the link between pain and allergy has been debated for decades, yet growing evidence suggests that allergic diseases, such as asthma and allergic rhinitis, may serve as risk factors for migraine in both adults and children. Moreover, allergic inflammation is also thought to contribute to neuropathic pain [131]. Finally, the potential pathophysiological overlap between allergic diseases and autism spectrum disorder (ASD) has been explored in both animal and human models. Growing evidence strongly suggests that maternal or early-life allergic conditions may significantly increase the risk of developing ASD later in life.

In conclusion, larger, well-designed studies are needed to better understand the bidirectional relationship between these diseases, as it may have significant clinical implications for treatment strategies and patient outcomes.